RESUMEN
Lysyl oxidase-like 3 (LOXL3), belonging to the lysyl oxidase family, is responsible for the crosslinking in collagen or elastin. The cellular localization of LOXL3 is in the extracellular space by reason of its canonical function. In tumors, the presence of LOXL3 has been associated with genomic stability, cell proliferation, and metastasis. In silico analysis has shown that glioblastoma was among tumors with the highest LOXL3 expression levels. LOXL3 silencing of U87MG cells by siRNA led to the spreading of the tumor cell surface, and the transcriptome analysis of these cells revealed an upregulation of genes coding for extracellular matrix, cell adhesion, and cytoskeleton components, convergent to an increase in cell adhesion and a decrease in cell invasion observed in functional assays. Significant correlations of LOXL3 expression with genes coding for tubulins were observed in the mesenchymal subtype in the TCGA RNA-seq dataset of glioblastoma (GBM). Conversely, genes involved in endocytosis and lysosome formation, along with MAPK-binding proteins related to focal adhesion turnover, were downregulated, which may corroborate the observed decrease in cell viability and increase in the rate of cell death. Invasiveness is a major determinant of the recurrence and poor outcome of GBM patients, and downregulation of LOXL3 may contribute to halting the tumor cell invasion.
Asunto(s)
Aminoácido Oxidorreductasas/metabolismo , Adhesión Celular , Regulación Neoplásica de la Expresión Génica , Glioblastoma/enzimología , Aminoácido Oxidorreductasas/genética , Aminoácido Oxidorreductasas/fisiología , Línea Celular Tumoral , Proliferación Celular , Simulación por Computador , Citoesqueleto/metabolismo , Endocitosis , Matriz Extracelular/metabolismo , Perfilación de la Expresión Génica , Glioblastoma/genética , Glioblastoma/patología , Glioblastoma/fisiopatología , Humanos , Lisosomas/fisiología , Invasividad NeoplásicaRESUMEN
Lysyl oxidase like 3 (LOXL3) is a copper-dependent amine oxidase responsible for the crosslinking of collagen and elastin in the extracellular matrix. LOXL3 belongs to a family including other members: LOX, LOXL1, LOXL2, and LOXL4. Autosomal recessive mutations are rare and described in patients with Stickler syndrome, early-onset myopia and non-syndromic cleft palate. Along with an essential function in embryonic development, multiple biological functions have been attributed to LOXL3 in various pathologies related to amino oxidase activity. Additionally, various novel roles have been described for LOXL3, such as the oxidation of fibronectin in myotendinous junction formation, and of deacetylation and deacetylimination activities of STAT3 to control of inflammatory response. In tumors, three distinct roles were described: (1) LOXL3 interacts with SNAIL and contributes to proliferation and metastasis by inducing epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma cells; (2) LOXL3 is localized predominantly in the nucleus associated with invasion and poor gastric cancer prognosis; (3) LOXL3 interacts with proteins involved in DNA stability and mitosis completion, contributing to melanoma progression and sustained proliferation. Here we review the structure, function and activity of LOXL3 in normal and pathological conditions and discuss the potential of LOXL3 as a therapeutic target in various diseases.
Asunto(s)
Aminoácido Oxidorreductasas/genética , Artritis/genética , Fisura del Paladar/genética , Enfermedades del Tejido Conjuntivo/genética , Matriz Extracelular/genética , Pérdida Auditiva Sensorineural/genética , Miopía/genética , Neoplasias/genética , Desprendimiento de Retina/genética , Aminoácido Oxidorreductasas/química , Aminoácido Oxidorreductasas/metabolismo , Artritis/enzimología , Artritis/patología , Fisura del Paladar/enzimología , Fisura del Paladar/patología , Colágeno/química , Colágeno/genética , Colágeno/metabolismo , Enfermedades del Tejido Conjuntivo/enzimología , Enfermedades del Tejido Conjuntivo/patología , Elastina/química , Elastina/genética , Elastina/metabolismo , Transición Epitelial-Mesenquimal/genética , Matriz Extracelular/química , Matriz Extracelular/enzimología , Regulación de la Expresión Génica , Pérdida Auditiva Sensorineural/enzimología , Pérdida Auditiva Sensorineural/patología , Humanos , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/metabolismo , Miopía/enzimología , Miopía/patología , Neoplasias/enzimología , Neoplasias/patología , Especificidad de Órganos , Desprendimiento de Retina/enzimología , Desprendimiento de Retina/patología , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Factores de Transcripción de la Familia Snail/genética , Factores de Transcripción de la Familia Snail/metabolismoRESUMEN
Glioblastoma (GBM) is the most aggressive type of brain tumor, with an overall survival of 17 months under the current standard of care therapy. CD99, an over-expressed transmembrane protein in several malignancies, has been considered a potential target for immunotherapy. To further understand this potentiality, we analyzed the differential expression of its two isoforms in human astrocytoma specimens, and the CD99 involved signaling pathways in glioma model U87MG cell line. CD99 was also analyzed in GBM molecular subtypes. Whole transcriptomes by RNA-Seq of CD99-siRNA, and functional in vitro assays in CD99-shRNA, that are found in U87MG cells, were performed. Astrocytoma of different malignant grades and U87MG cells only expressed CD99 isoform 1, which was higher in mesenchymal and classical than in proneural GBM subtypes. Genes related to actin dynamics, predominantly to focal adhesion, and lamellipodia/filopodia formation were down-regulated in the transcriptome analysis, when CD99 was silenced. A decrease in tumor cell migration/invasion, and dysfunction of focal adhesion, were observed in functional assays. In addition, a striking morphological change was detected in CD99-silenced U87MG cells, further corroborating CD99 involvement in actin cytoskeleton rearrangement. Inhibiting the overexpressed CD99 may improve resectability and decrease the recurrence rate of GBM by decreasing tumor cells migration and invasion.
